Research in our laboratory is concerned with the ionic channels in nerve and muscle membranes that are responsible for electrical signaling. In one series of recent experiments we have investigated the possible involvement of arginine residues with the process of inactivation in sodium channels. Application of 4 mM n-propylguanidinium (nPG) inside axons results in a speeding of inactivation kinetics and a reduction in peak sodium conductance. These phenomena have been studied extensively and a kinetic model developed to explain the dependence of drug action on voltage, sodium concentration gradient, drug concentration and temperature. Further experiments, including mesurements of gating currents, are planned. We are also investigating the mode of action of local and general anesthetics. nPG may act as a receptor common to that of local anesthetics. Ether and halothane are studied at clinically relevant concentrations. They also speed sodium channel inactivation, but by a mechanism quite different from that of nPG. We are investigating the interrelationship of axons and satellite cells, in an attempt to determine the spatial distribution of sodium and potassium channels. This work will be done in both unmyelinated and in myelinated neurons. This proposal thus seeks basic information on excitable membrane function and on the mechanism of neuropharmacological and neurotoxic compounds.